protofibrils

Protofibrils are elongated, partially ordered assemblies that form during the aggregation of proteins that misfold and accumulate into amyloid structures. They are commonly described as intermediates between smaller oligomeric species and mature amyloid fibrils. Protofibrils often exhibit higher beta-sheet content and longer, more extended morphologies than oligomers, but are less uniform and less mature than canonical fibrils; their exact structure can vary by protein and experimental conditions. In many systems, protofibrils can interact with membranes and may form pore-like structures, contributing to cellular dysfunction.

Protofibrils have been studied in the context of several neurodegenerative diseases. Amyloid beta protofibrils are a major focus in Alzheimer's disease, and similar pre-fibrillar species have been described for alpha-synuclein in Parkinson's disease, prion protein, and other amyloidogenic proteins. They are frequently proposed to be highly toxic, capable of disrupting membrane integrity, perturbing calcium homeostasis, and impairing synaptic function. Protofibrils can also act as seeds that accelerate further aggregation and may participate in cross-seeding between different proteins, potentially supporting prion-like spread in the brain.

Detection and characterization of protofibrils employ techniques such as transmission electron microscopy, atomic force microscopy, cryo-electron microscopy, and spectroscopic methods, along with conformation-specific antibodies and dye assays. They have been observed in in vitro aggregation assays and in biological samples, including cerebrospinal fluid and brain tissue. Terminology varies in the literature, with some authors distinguishing protofibrils from oligomers and others using protofibril to describe any pre-fibrillar aggregate. Protofibrils are an active area of research due to their potential roles in disease mechanisms and as therapeutic targets and biomarkers.